Antibodies are a class of proteins produced by an organism in response to the invasion of foreign compounds called antigens. The antibodies produced characteristically bind to the antigens in a highly specific manner to initiate protection against infection or disease. The human body is capable of synthesizing more than a million different types of antibody molecules.
Each antibody or immunoglobulin molecule is composed of four polypeptide chains of two different kinds: a pair of identical high-molecular-weight chains, called "heavy" or "H" chains, and a pair of identical lower-molecular-weight chains called "light" or "L" chains. Each of the four polypeptide chains that form the monomeric immunoglobulin G (IgG) molecule is divided into separate regions called "domains." There are two domains in the L chains and four domains in the H chains. Within each of the domains, folding of the polypeptide chain produced two parallel planes, each containing several segments with folded beta structure. Among the IgG class, certain domains of both the H and L chains are homologous or constant and certain domains are variable. Each L chain has one variable and one constant domain; each H chain has one variable and three constant domains. The variable domains occur near the amino-terminus of the polypeptide chains and together create an antigen-binding site that is unique to that IgG molecule. The variable domain of each light chain is designated V.sub.L and the constant domain C.sub.L. The variable domain of a heavy chain is designated V.sub.H and the constant regions C.sub.H 1, C.sub.H 2, C.sub.H 3.
At the level of primary amino acid sequence, each variable region of an antibody is composed of four framework regions interspersed with three hypervariable regions, also known as complimentarity determining regions (CDRs). The three-dimensional structure of the framework regions comprise an array of anti-parallel .beta.-sheets, from which project loop-shaped CDRs. Differing patterns of loop sizes from one antibody to another establish the gross topography of variable regions, combining with the effect of amino acid sequence diversity to generate antibody specificities.
Studies in which antibodies have been co-crystallized with bound antigen indicate that the CDRs are involved in antigen binding. Recent studies using synthetic peptides derived from antibody CDRs confirm that these structures are involved in contacting the antigen, and indicate that the chemical nature of specific amino acids is critical in determining binding specificity.
Given their demonstrated reactivity, antibodies would appear to be quite useful in programs for the treatment of disease. However, successful clinical therapies involving the provision of antibodies produced outside the human body have yet to be successfully developed, despite the considerable progress which recently has been made in monoclonal production techniques. One significant impediment to antibody therapies is the fact that any given antibody is itself an antigen which elicits the production of antibodies to itself, called anti-idiotypic antibodies, through an immune response. It has been found, for example, that administering antibody-containing compositions frequently produces serum sickness or other side effects. Therapeutic approaches also are complicated by the basic chemical instability of most antibodies.
Recent advances in genetic engineering, immunoglobulin sequence analysis, x-ray crystallography, and computer-assisted molecular modeling have greatly facilitated the design of potentially improved antibodies. These technical advances have also spurred considerable research activity in compositions which react in the same manner as antibodies Vet which do not themselves elicit an immune response. Certain synthetic peptides derived from CDR sequences have been shown to possess properties which are similar to the intact antibody in that they can inhibit idiotype-antiidiotype interactions, bind specific antigens, interact with cellular receptors, and stimulate biological processes. For example, Williams, et al., Proc. Natl. Acad. Sci. U.S.A., 1989, 86, 5537, disclose that a biologically active peptide derived from the second complementarity region of the monoclonal antibody 87.92.6 light chain variable region can bind to the reovirus type 3 receptor and inhibit DNA synthesis in a manner similar to the antibody. Williams, et al. additionally identify specific amino acid residues and structural features involved in producing these effects, and suggest that short, nonimmunogenic peptides modeled after the hypervariable regions of antibodies may lead to the development of biologically active substances having clinical utility. However, clinical applications for such peptides are complicated by, for example, concerns of chemical instability, bioavailability, proteolytic degradation, and oral inactivity. In addition, peptides are generally not able to cross lipid membrane barriers such as the blood-brain barrier.